A simple heterocyclic fusion reaction and its application for expeditious syntheses of rutaecarpine and its analogs

Article abstract of DOI:10.1016/j.tetlet.2014.04.120

In the search for new inhibitors of cholinesterases, a simple heterocyclic fusion reaction of isatoic anhydride 8 and 3,4-dihydroisoquinoline 22 was discovered which involves a spontaneous dehydrogenation upon heating. Applying the reaction, the bioactive natural alkaloid rutaecarpine and several substituted derivatives out of tryptamines and anthranilic acids or isatoic anhydrides, respectively, can be synthesized without tedious chromatographic purification. This provides simple and fast access to larger amounts of compounds with this privileged structure in medicinal chemistry.

Full text of DOI:10.1016/j.tetlet.2014.04.120

Accepted Manuscript
A Simple Heterocyclic Fusion Reaction and its Application for Expeditious
Syntheses of Rutaecarpine and its Analogs
Guozheng Huang, Dominika Roos, Patricia Stadtmüller, Michael Decker
PII:
S0040-4039(14)00757-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.120
TETL 44582
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 March 2014
28 April 2014
30 April 2014
Please cite this article as: Huang, G., Roos, D., Stadtmüller, P., Decker, M., A Simple Heterocyclic Fusion Reaction
and its Application for Expeditious Syntheses of Rutaecarpine and its Analogs, Tetrahedron Letters (2014), doi:
http://dx.doi.org/10.1016/j.tetlet.2014.04.120
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Tetrahedron Letters
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Tetrahedron Letters
jo u rna l ho me pa g e : ww w .e lsevier .co m/ lo ca te /te tle t
A Simple Heterocyclic Fusion Reaction and its Application for Expeditious
Syntheses of Rutaecarpine and its Analogs
Guozheng Huang, Dominika Roos, Patricia Stadtmüller and Michael Decker∗
Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität, Am Hubland, D-97074
Würzburg, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Abstract—In the search for new inhibitors of cholinesterases, a simple heterocyclic fusion
reaction of isatoic anhydride 8 and 3,4-dihydroisoquinoline 22 was discovered which
involves a spontaneous dehydrogenation upon heating. Applying the reaction, the bioactive
natural alkaloid rutaecarpine and several substituted derivatives out of tryptamines and
anthranilic acids or isatoic anhydrides, respectively, can be synthesized without tedious
chromatographic purification. This provides simple and fast access to larger amounts of
compounds with this privileged structure in medicinal chemistry.
Revised
Accepted
Available online
Keywords:
Rutaecarpine
Total synthesis
Isatoic anhydride
Dehydrogenation
2014 Elsevier Ltd. All rights reserved.
Quinazolinones are among the so-called privileged
molecules for drug discovery. Natural and synthetic
quinazolinones have been described to possess diverse
biological activities including anticancer, antiinflammatory,
antimalarial, antiviral, antioxidant, CNS depressant and
several other activities.1
Rutaecarpine (1a, Figure 1) is a natural quinazolino
carboline-type alkaloid first isolated in 1915 from Evodia
rutaecarpa2 which is used in Traditional Chinese Medicine
as a herbal remedy for the treatment of inflammation-
related disorders.3,4 Later, it was also separated from other
plant families such as Horita, Zanthoxylum, Euxylophorea,
and several others. A couple of natural derivatives of
rutaecarpine (1b-1j) bearing hydroxy and methoxy groups
at ring A or E also have also been isolated from various
plants.1a, 3, 5
Accumulating research has proven useful biological
properties of rutaecarpine 1a and its natural and synthetic
analogs, such as anti-platelet aggregation,6 vasorelaxing,7
antiobesity,8 cytotoxity,9 and cyclooxygenase-2 inhibitory
activitiy.10
Its multiple biological activities intrigued many efforts on
the syntheses of 1a and its analogs, which are – despite the
simplicity of the pentacyclic structure - in most cases far
from being effortless.11 Briefly, these syntheses can be
divided into four distinct types: (1) using derivatives of
Figure 1. Structures of rutaecarpine and its naturally occurring
derivatives
———
∗ Corresponding author: Michael Decker, Tel.: 0049-931-31-89676,
E-Mail: michael.decker@uni-wuerzburg.de

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anthranilic acid (2-9, Figure 2) and tryptamine (10-17,
Figure 3) to build the D ring or C, D rings simultaneously
Our group has developed several novel inhibitors of both
acetyl- and butyrylcholinesterase derived from
dehydroevodiamine and rutaecarpine 1a.17 A structure like
compound 20 represents selective inhibitor of
12
at the final stage;
intermediate
6,11(7H)-dione via different schemes, then applying
(2) first synthesis of the tricyclic
8,9-dihydro-6H-pyrido[2,1-b]quinazoline-
a
acetylcholinesterase for putative treatment of Alzheimers’
disease.17a During our search for new inhibitors of
cholinesterases, compound 23 (the benzo-analog of the
alkaloid evodiamine) was synthesized by condensation of
N-methyl isatoic anhydride 21 and 3,4-dihydroisoquinoline
22 in toluene under reflux in moderate yield (Scheme 2).17d
Reacting the related unsubstituted isatoic anhydride 8 with
22, the expected molecule would be compound 24.18
Surprisingly, compound 25a formed as confirmed by its
spectral data (Scheme 3).15b, 17a, 19
13
Fischer indole synthesis as the final step;
(3) pre-
obtaining the reduced structure of rutaecarpine, then
oxidation to achieve the target structure;14 (4) metal
catalyzed or radical cyclization to form C ring as the key
step.15 Also methods outside these categories have been
described.16
We assumed compound 24 occurs as the intermediate
during the reaction, which dehydrogenates spontaneously
upon heating to be converted into 25a. The same
spontaneous dehydrogenation also occurred in the so-called
retro mass-spectral synthesis of 1a in Kametani’s group.12e
Che et al. used aryl azides 5 as nitrogen source for C–N
bond formation, compounds 24 and 25a were obtained in
the same reaction with yield of 73% and 9%, respectively.19
Figure 2. Structures of anthranilic acid and its derivatives applied
as synthones of rutaecarpine
Usually, activated derivatives of anthranilic acid and
tryptamine represent the reactive forms of the two starting
materials. For example, compounds 3 and 15 were utilized
by Asahina et al. in 1927 for the first synthesis of
rutaecarpine 1a.12a
Scheme 2. The structure of acetylcholinesterase inhibitor 20 and
synthesis of the benzo-evodiamine 23
O
O
O
N
N
N
H
O
N
N
8
22
25a
-H2
O
O
-CO2
N
Figure 3. Structures of tryptamine and its derivatives applied as
synthones of rutaecarpine
N
NH
H
24
O
O
Generally, all these methods are multi-step synthetic
procedure, require special reagents and/or starting materials
and therefore lead to small quantities of the target
structures, often not enough for further pharmacological
evaluations. Up to now, probably one of the most effective
methods (Scheme 1) is Bergman’s synthesis, which uses
compound 9 and tryptamine 10 to form the intermediate 18.
Treatment of intermediate 18 under acidic condition
achieves the closure of ring C and formation of 19, which
loses CHF3 to yield compound 1a. In this method,
rutaecarpine could be obtained from compounds 9 and 10
in less than 1 hr via 3 steps in almost quantative yield.12g
Scheme 3. Synthesis of the benzo-rutaecarpine 25a
Our pilot reaction achieved the unexpected benzo-
rutaecarpine 25a in moderate yield (50%). We assumed
that the relatively low yield resulted from incomplete
conversion of compound 24 to 25a in toluene and we
monitored the reaction progress by HPLC. Running the
reaction in THF also encountered the same problem while
in DMF conversion was completed with concomitant
increased yield.
Scheme 1. Bergman’s synthesis of 1a.12g Reagents and conditions:
a) pyridine; b) HCl, AcOH; c) KOH, EtOH

Tetrahedron Letters
3
triphosgene in theoretical yield. The isatoic anhydrides
were then mixed with 16 or 22 in DMF and heated at 95 °C
overnight. Water was added to the cooled reaction mixture,
and then the desired products precipitated and collected by
filtration with good to excellent yield (69 - 96%, Table 1).
Normally the substituted group on ring E did not influence
the reaction. Without protection of the hydroxy group,
compound 1i and 25c could be obtained smoothly, which
proved free OH groups do not trouble the reaction process.
Electron donating or withdrawing groups also did not
deteriorate the yield: 3-Nitrorutaecarpine 1n was obtained
in similar yield as 3-benzoxyrutaecarpine 1k.
Scheme 4. Syntheses of 1a and its analogs
Since 25a bears a closely related quinazolinone structure to
rutaecarpine, it is reasonable to apply this method to
synthesize 1a and its analogs. A mixture of isatoic
anhydride 8 and 4,9-dihydro-3H-pyrido[3,4-b]indole 16
(which can be synthesized from tryptamine via a 2-step
scheme in quantitative yield without chromatographic
purification20), was stirred in DMF at 95 °C for 20 hrs to
afford 1a in 93% yield.
Compound 1p had previously been synthesized by Daïch et
al., but only in 39% yield.
12i
Our method drastically
improves the yield and even avoids any chromatographic
purification. 1-Methoxyrutaecarpine (1h) was separated
from Zanthoxylum integrifoliolum and showed anti-platelet
aggregation activity, but had never been synthesized in a
lab.6 Our method therefore completed the first total
synthesis of 1h. This method can also be easily applied in
the total synthesis of 1b-1g when appropriate 2-
aminobenzoic acids are available.
It is noticeable that both simple isatoic anhydride 8 and 16
were utilized in the synthesis of 1a. Bergman et al.
converted 8 into 9 for their effective synthesis.12g Chavan et
al. used 8 as starting material via 6-step synthesis to give
8,9-dihydro-6H-pyrido[2,1-b]quinazoline-6,11(7H)-dione,
which was subjected to the Fischer indole synthesis to yield
1a.13f Also 16 (together with 6) appeared in Kametani
group’s synthesis.12e Nevertheless, to our knowledge, both
8 and 16 are not applied in the same reaction.
In conclusion, here we described a novel, short and
versatile method for expeditious syntheses of rutaecarpine
and its analogs giving high yields and devoid of tedious
purification procedures. Unlike previously described
procedures, neither multi-step syntheses nor special
reagents are necessary, and no special starting materials
have to be prepared prior to the synthesis. Applying this
fusion reaction, 20 compounds were obtained. Elucidation
of putative cytotoxicity9 of the compounds obtained is
ongoing and will be reported soon.
Compounds
1a (rutaecarpine)
Yield
93%
72%
89%
75%
85%
83%
75%
78%
96%
79%
83%
77%
91%
86%
81%
69%
94%
89%
76%
79%
R or X
R1 = R2 = R3 = H
25a
1h (1-methoxyrutaecarpine)
R1 = OCH3,
R2 = R3 = H
25b
1i (3-hydroxyrutaecarpine)
Acknowledgments
R1 = R2 = H,
R3 = OH
25c
We thank Jan Glaser for his help on measuring the ESI-MS
of the compounds. M. Decker gratefully acknowledges the
German Science Foundation (DFG) for financial support
(DFG DE 1546/6-1).
1j (euxylophoricine A)
R1 = H,
R2 = R3 = OCH3
25d
1k (3-benzyloxyrutercarpine)
R1 = R2 = H,
R3 = OBn
25e
1l (3-chlororutaecarpine)
R1 = R2 = H,
R3 = Cl
25f
Supplementary Data
1m (1-bromo-3-methylrutaecarpine)
R1 = Br, R2 = H,
R3 = CH3
25g
Supplementary data (experimental procedures and spectral
data for the intermediate isatoic anhydrides, 1a, 1i–1q, 25a-
25j) associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tetlet
1n (3-nitrorutaecarpine)
R1 = R2 = H,
R3 = NO2
25h
1o
X=CH
X=N
25i
1p
References
25j
Table 1. Overall yield for the synthesis of rutaecarpine and its
analogs (for assignment of structures cf. Scheme 4)
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Tetrahedron Letters
5
O
R
3
N
D
N
E
C
R2
B
R4
HN
R1
A
1a
1b
1c
1d
1e
1f
1g
1h
1i
R1 = R2 = R3 = R4 = H (rutaecarpine)
R1 = R2 = R3 = H, R4 = OCH3 (hortiacine)
R1 = H, R2 = R3 = OCH2O, R4 = H (euxylophoricine C)
R1 = H, R2 = R3 = R4 = OCH3 (euxylophoricine D)
R1 = OH, R2 = R3 = R4 = H (1-hydroxyrutaecaprine)
R1 = H, R2 = OCH3, R3 = R4 = H (2-methoxyrutaecaprine)
R1 = R2 = OH, R3 = R4 = H (1,2-dihydroxyrutaecaprine)
R1 = OCH3, R2 = R3 = R4 = H (1-methoxyrutaecaprine)
R1 = R2 = H, R3 = OH, R4 = H (3-hydroxyrutaecaprine)
R1 = H, R2 = R3 = OCH3, R4 = H (euxylophoricine A)
1j

6
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Tetrahedron Letters
7

8
Tetrahedron Letters

Tetrahedron Letters
9

10
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11

12
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A Simple Heterocyclic Fusion Reaction and
its Application for Expeditious Syntheses of
Rutaecarpine and its Analogs
Guozheng Huang, Dominika Roos, Patricia Stadtmüller, and Michael Decker*